Obesity-related Modulation of Radiation Responses in the Mouse Liver: the Role of miRNAs

Obesity and associated disorders are increasingly becoming a global health challenge. Obesity is a major risk factor for various metabolic syndromes (such as insulin resistance, type 2 diabetes and nonalcoholic fatty liver disease) and for initiation of cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and obesity-related metabolic disorders. In high-fat diet-fed obese C57BL/6J mice, we observed the repression of several liver cancer-associated genes through promoter methylation. Radiation-triggered microRNA modulations observed in normal mice were not observed in obese mice. In non-irradiated obese mice, miR-466e was upregulated and several of its putative target genes were repressed. In order to mimic in vitro the effects of obesity on radiation responses in the mouse liver, we treated AML12 murine liver cells with free fatty acids (FFAs: palmitic acid and oleic acid). Twelve hours after FFA treatment, ROS levels increased significantly, reminiscing of chronic oxidative stress in C57BL/6J mouse livers. Free fatty acid administration sensitized AML12 mouse liver cells to ionizing radiation, but the inhibition of miR-466e counteracted this radio-sensitization, suggesting that the modulation of radiation responses by diet-induced obesity might involve miR-466e expression. All together, our results suggest the existence of dietary effects on radiation responses (especially epigenetic regulations) in the liver, possibly in relationship with obesity-induced chronic oxidative stress.日本放射線影響学会第57回大